Huntington's disease (HD) is a hereditary neurodegenerative disorder that produces choreoathetosis, dementia and psychosis and affects about 30,000 individuals in the United States. One potential treatment strategy for HD involves the replacement of injured or dead neurons by stimulating the proliferation of endogenous neuronal precursors and their migration into damaged brain regions. An increase in the number of cells that express cell-proliferation and immature neuronal markers has been observed in the subventricular zone (SVZ) adjacent to the caudate nucleus in brains of patients with HD. Given this finding, and because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we have treated HD transgenic R6/2 mice with subcutaneous fibroblast growth factor-2 (FGF-2), and found that FGF-2 increased the number of bromodeoxyuridine (BrdU)-labeled, doublecortin (DCX)-expressing cells in the SVZ by ~30% in wild-type mice, and by ~150% in HD transgenic R6/2 mice. FGF-2 also induced recruitment of new neurons from the SVZ into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these new neurons were DARPP-32-expressing cells with properties of medium spiny neurons and pallidal projections, consistent with the phenotype of neurons lost in HD. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by ~20%. We hypothesize that FGF-2, and perhaps other growth factors, can stimulate new neurons in the SVZ to proliferate, transit into striatum and cortex, develop functional properties of mature neurons, and integrate into brain circuitry to help offset HD-related deficits. We also hypothesize that functional outcome in HD will be improved by administration of neurogenesis-promoting factors. We will test these hypotheses with the following Specific Aims: (1) Determine the manner in which expression of expanded mutant human Htt in transgenic mice affects neuronal precursor cells in the adult SVZ with FGF-2 treatment. (2) Establish the migratory destinations and functional fate of newborn neurons in adult R6/2 HD-transgenic mice with FGF-2. (3) Examine the role of FGF-2-induced neurogenesis in ameliorating the transgenic HD phenotype. (4) Determine if other neurogenesis-promoting growth factors, or FGF-2 combined with other growth factors, improve the phenotype and survival of R6/2 HD transgenic mice to a greater extent than FGF-2 alone.We are developing a potential therapy to protect neurons or replace them in Huntington's disease.